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Biology subjects

Cao, P.

Publications and source records attributed to Cao, P..

At least 37 records · Page 2Linked to original sources

General purpose genotypes and evolution of higher plasticity in clonality underlie knotweed invasion

Many widespread invasive plant species express high phenotypic variation across novel environments, providing a unique opportunity to examine ecological and evolutionary dynamics under global change. However, biogeographical studies often lack information about the origin of introduced populations, limiting our understanding of post-introduction evolution of introduced species in the new range. Here, we assessed the responses of Reynoutria japonica from 128 populations spanning three latitudinal transects in the native ranges of China and Japan, and the introduced ranges of North America and Europe. When grown in two common gardens in the native range, plants from introduced populations in North America and Europe differed in almost all traits from those from native Chinese populations, but were similar to plants from native Japanese populations. Compared to Chinese populations, North American, European and Japanese populations expressed lower trait values and plasticity in most traits. However, plants from both introduced ranges and from Japanese populations expressed higher clonality and plasticity in clonality than plants from Chinese populations. In addition, introduced populations expressed higher plasticity in clonality but lower plasticity in basal diameter compared to Japanese populations. Our study showed heritable differences in phenotypes between plants from the native ranges of Japan and China, and those from the introduced ranges were similar to the putative source of origin in Japan. However, we found that introduced populations may have evolved higher plasticity in clonal growth. Our findings emphasize the critical role of clonality and plasticity in invasion success, demonstrating the importance of discriminating between source and non-source native populations to identify ecological and evolutionary responses of invasive plants to novel environments.

ecology↗

Olfactory cortical outputs recruit and shape distinct brain-wide spatiotemporal networks

Odor information is transmitted from the olfactory bulb to several primary olfactory cortical regions in parallel, including the anterior olfactory nucleus (AON) and piriform cortex (Pir). However, the specific roles of the olfactory bulb and cortical outputs in wider interactions with other interconnected regions throughout the brain remain unclear due to the lack of suitable in vivo techniques. Furthermore, emerging associations between olfactory-related dysfunctions and neurological disorders underscore the need for examining olfactory networks at the systems level. Using optogenetics, fMRI, and computational modeling, we interrogated the spatiotemporal properties of brain-wide neural interactions in olfactory networks. We observed distinct downstream recruitment patterns. Specifically, stimulation of excitatory projection neurons in OB predominantly activates primary olfactory network regions, while stimulation of OB afferents in AON and Pir primarily orthodromically activates hippocampal/striatal and limbic networks, respectively. Temporally, repeated OB or AON stimulation diminishes neural activity propagation brain-wide in contrast to Pir stimulation. Dynamic causal modeling analysis reveals a robust inhibitory effect of AON outputs on striatal and limbic network regions. In addition, experiments in aged rat models show decreased brain-wide activation following OB stimulation, particularly in the primary olfactory and limbic networks. Modeling analysis identifies a dysfunctional AON to Pir connection, indicating the impairment of this primary olfactory cortical circuit that disrupts the downstream long-range propagation. Our study delineates the spatiotemporal properties of olfactory neural activity propagation in brain-wide networks for the first time and distinguishes the roles of primary olfactory cortical, AON and Pir, outputs in shaping neural interactions at the systems level.

neuroscience↗

Modeling Repertoire Behavior within the Energy-Based Framework: A Study on Cell Proliferation and Somatic Hypermutation during the Adaptive Immune Response

Monitoring and describing the adaptive immune repertoire(IR) for disease detection and diagnosis is essential in healthcare research. Many phenomenon have been observed to generalize the static property of IR, but the mathematical description of the formation and dynamic changes of IR still lacks research. Here, we present a mathematical and physical model to interpret the cell proliferation and somatic hypermutation(SHM) process in IR, difficulties to generate different clones in IR are computed, and IR distance is calculated as the minimum effort required to transform one IR distribution to another. IR distribution and distance can be detected from samples containing 104 cells. The validity of our method is confirmed by the unsupervised clustering of data from mice spleen and clinical PBMC samples including various immune stages and diseases. Our work dynamically characterize and quantify IR process, enabling a macroscopic immunoevaluation by sensitive immune fluctuation detection from minute samples.

biophysics↗

Natural selection and evolution of mitochondrial genome in terrestrial and aquatic turbellarians

Mitochondrial energy metabolism may be directly influenced by natural selection pressures in response to the energy demands of an organisms specific ecological niche. Here, we hypothesized that the mitochondrial genome of turbellarian animals was influenced by the metabolic requirements of various habitats We used selection pressure and phylogenetic independent contrasts (PIC) analyses to detect the selection pressure of protein-coding genes in the mitochondrial genome of turbellarian living in aquatic and terrestrial habitats. The results indicated turbellarians in aquatic habitats experienced greater selection pressure, resulting in the evolution of several genes at a lower {omega} value compared to their terrestrial counterparts. The NAD4 was identified as having positive selection sites in all site models analyzed. Among all genes, the equilibrium constant (ionization of COOH) was the most frequently detected amino acid characteristic with significant positive selection changes, followed by hydropathy and molecular volume. The equilibrium constant (ionization of COOH) was found to be the amino acid characteristic with the greatest magnitude of change in NAD4. This suggests that it plays a crucial role in the adaptive evolution of turbellarians to varying habitats. The study found a significant positive correlation (R = 0.61, p < 0.05) between the {omega} value of turbellarian and their habitats by PIC analysis. These findings shed light on the adaptive evolution of turbellarian mtDNAs and their influence on the oxidative phosphorylation molecular mechanism. 0. Significance statementThe adaptive evolution of mitochondrial genes is closely related to environmental temperature, high energy metabolism demand, altitude, and oxygen availability. Mitochondrial energy metabolism may be directly influenced by natural selection pressures in response to the energy demands of an organisms specific ecological niche. Here, we investigated the evolution of mtDNA PCGs in turbellarians across different habitats, and identified purifying selection as the main evolutionary pattern of the turbellarian mitochondrial genome. Additionally, we found that NAD4 played an important role in the adaptive evolution of turbellarians to different habitats.

evolutionary biology↗

Curved light sheet microscopy for centimeter-scale cleared tissues imaging

Imaging large cleared tissues requires scaling the throughput of imaging techniques. Here we introduce curved light sheet microscope to perform optical sectioning with curved light sheets. This concept addresses the long-standing field curvature problem and lowers the barriers in designing high-throughput objectives. Leveraging a customized objective, the curved light sheet microscope achieves diffraction-limited resolution (1.0 m laterally and 2.5 m axially) and uniform contrast over a field of view of more than 1 x 1 cm2 and is compatible with various tissue clearing techniques. Imaging an entire intact cleared mouse brain at 0.625 x 0.625 x 1.25 m3 voxel size takes less than 3 hours and image tiling is not required. We share full optics description of the objective and report imaging neuronal and vascular networks and tracing brain-wide long-distance axonal projections in intact mouse brains.

bioengineering↗

Restoring O-glycosylation and expression of MUC2 limits progression of colorectal cancer

This study investigated the molecular mechanisms underlying the regulation of MUC2 expression and O-glycosylation modification in colorectal cancer. In addition, the potential of rosiglitazone to inhibit colorectal cancer by improving MUC2 glycosylation to protect intestinal barrier function was explored. In vitro, lectin staining combined with Co-IP assay was used to detect glycosyltransferases regulating MUC2 O-glycosylation. ChIP and Luciferase experiments were used to verify the transcription factors regulating MUC2 expression level. Samples from CRC patients were used to detect differences in multimolecular expression. The AOM/DSS mouse model was used to validate the effect of rosiglitazone on inhibiting colorectal cancer progression. Our results showed that B3GNT6 acts as a glycosyltransferase to enhance the O-glycosylation level of MUC2 and maintain protein stability to resist degradation by StcE secreting from pathogenic bacteria. Furthermore, KLF4 directly promotes the transcription of B3GNT6 and MUC2, which are regulated by PPARg. Rosiglitazone activated PPARg-KLF4-B3GNT6 axis which increased the expression level and glycosylation of MUC2 and further improved the intestinal mucosal barrier function to delay the development of colorectal cancer in mice. These data suggest that O-glycosylation and expression of MUC2 is key to the maintenance of functional intestinal mucosa and rosiglitazone is a potential colorectal cancer therapeutic agent.

cancer biology↗

Divergence in herbivore resistance during the invasion of a global plant invader

O_LISuccessful plant invasions are often explained with adaptation to novel environments. However, invasive species often occupy broad niches within their native and introduced ranges, and a true understanding of microevolution during invasion therefore requires broad sampling of ranges, ideally with a knowledge of introduction history. C_LIO_LIWe tested for genetic differentiation in herbivore resistance among 128 introduced (Europe, North America) and native (China, Japan) populations of the invasive Japanese knotweed (Reynoutria japonica) in two common gardens in the native range. C_LIO_LIIn both common gardens we found that resistance traits of introduced populations differed from most Chinese native populations, but not from populations in Japan, the putative sources of introduction. Compared to Chinese populations, introduced European populations had thicker leaves with a lower C:N ratio but higher flavonoids contents. In the native range, variation in herbivore resistance was much more strongly associated with climate of origin than in introduced populations. C_LIO_LIOur results support the idea that founder effects played a key role in the invasion of knotweed into Europe and North America, with introduction of particular resistance phenotypes from Japan. Our study also demonstrates how knowledge of introduction history can avoid drawing wrong conclusions from observed biogeographic divergence. C_LI

ecology↗

Characterisation of Plasmodium vivax lactate dehydrogenase dynamics in P. vivax infections

Plasmodium vivax lactate dehydrogenase (PvLDH) is an essential enzyme in the glycolytic pathway of Plasmodium vivax. It can also be used as a diagnostic biomarker. Quantitation of plasma PvLDH has been used as a measure of P. vivax biomass in clinical studies of uncomplicated and severe vivax malaria. With the increasing importance of PvLDH in studying P. vivax diagnosis and infection, improved characterisation of the dynamics of this biomarker is important. In this study, we developed mathematical models that capture parasite and matrix PvLDH dynamics in ex vivo culture and the human host. We estimated the biological parameters using ex vivo and in vivo longitudinal data of parasitemia and PvLDH concentration collected from P. vivax-infected humans using Bayesian hierarchical inference. We found that the ex vivo and in vivo estimates of PvLDH in a parasitized red blood cell differed significantly across the asexual life cycle, with in vivo estimates at least ten-fold higher than ex vivo estimates (for example, the median estimate of intraerythrocytic PvLDH mass at the end of the life cycle was 9.4x10-3 ng in vivo vs. 5.1x10-4 ng ex vivo). We also estimated the ex vivo PvLDH half-life to be 65.3 h (95% credible interval: 60.8--70.7 h), which is approximately three times longer than the median estimate of the in vivo PvLDH half-life, 21.9 h (16.7--29.9 h). Our findings provide an important foundation to further improve quantitative understanding of P. vivax biology and facilitate the development of PvLDH-based diagnostic tools.

biophysics↗

Tumor-specific neutrophils originating from meninges promote glioblastoma

Glioma is one of the most aggressive human cancers with limited therapeutic options. Though research has extensively examined immune components in those malignant tumors, the pathophysiological mechanism establishing their immunosuppressive microenvironment remains incompletely characterized. In this study, we report for the first time the unique presence of tumor-specific neutrophils (TSNs) in human glioblastoma (GBM) tumors. This newly defined neutrophil subtype exhibits the high expression of several immunosuppressive genes (e.g., CD274 and IDO1) and is strongly correlated with glioma grades and poor prognosis of patients. TSNs with comparable gene signatures are similarly present in the tumors but not bone marrow or spleen of mouse glioma models. Blockage of TSN recruitment by either Cxcl1-knockout in glioma cells or Cxcr2-deletion in host mice significantly enhances antitumor immunity and inhibits tumor progression. Surprisingly, we further identify the meninges as the key extratumoral source of generating TSNs in both human GBM patients and mouse glioma models. These results have elucidated a novel mechanism of neutrophils designating the tumor immune microenvironment and the essential link of meningeal immunity to glioma.

cancer biology↗

Multi-omics and Pharmacological Characterization of Patient-derived Glioma Cell Lines

Glioblastoma (GBM) is the most common brain tumor and is currently incurable. Primary GBM cultures are widely used tools for screening potentially therapeutic drugs; however, there is a lack of genomic and pharmacological characterization of these primary GBM cultures. Here, we collected 52 patient-derived glioma cell (PDGC) lines and characterized them through whole- genome sequencing (WGS), RNA-seq, and drug response screening. We identified three molecular subtypes among PDGCs: mesenchymal (MES), proneural (PN), and oxidative phosphorylation (OXPHOS). Upon profiling the responses of PDGCs to 214 drugs, we found that the PN subtype PDGCs were sensitive to tyrosine kinase inhibitors, whereas the OXPHOS subtype PDGCs were sensitive to histone deacetylase inhibitors, oxidative phosphorylation inhibitors, and HMG-CoA reductase inhibitors. PN and OXPHOS subtype PDGCs stably formed tumors in vivo upon intracranial transplantation into immunodeficient mice, while most MES subtype PDGCs were incapable of tumorigenesis in vivo. In addition, profiling and follow-up investigations showed that the serum-free culture system used for PDGCs enriched and propagated rare MYC/MYCN- amplified glioma cells. Our study provides a resource for understanding primary glioma cell cultures and aiding clinical translation. SignificanceOur study provides a resource for patient-derived glioma cell lines (PDGCs) on transcriptome, genome, drug response, and tumorigenic abilities. PDGCs are categorized into PN, MES, and OXPHOS subtypes, with MES-subtype PDGCs incapable of tumorigenesis in vivo. Notably, the serum-free culture system for PDGCs enriches glioma cells with MYC/MYCN amplification.

cancer biology↗

Enhanced viral infectivity and reduced interferon production are associated with high pathogenicity for influenza viruses

Epidemiological and clinical evidence indicates that humans infected with the 1918 pandemic influenza virus and highly pathogenic avian H5N1 influenza viruses often displayed severe lung pathology. High viral load and extensive infiltration of macrophages are the hallmarks of highly pathogenic (HP) influenza viral infections. However, it remains unclear what biological mechanisms primarily determine the observed difference in the kinetics of viral load and macrophages between HP and low pathogenic (LP) viral infections, and how the mechanistic differences are associated with viral pathogenicity. In this study, we develop a mathematical model of viral dynamics that includes the dynamics of different macrophage populations and interferon. We fit the model to in vivo kinetic data of viral load and macrophage level from BALB/c mice infected with an HP or LP strain of H1N1/H5N1 virus using Bayesian inference. Our primary finding is that HP viruses has a higher viral infection rate, a lower interferon production rate and a lower macrophage recruitment rate compared to LP viruses, which are strongly associated with more severe tissue damage (quantified by a higher percentage of epithelial cell loss). We also quantify the relative contribution of macrophages to viral clearance and find that macrophages do not play a dominant role in direct clearance of free virus although their role in mediating immune responses such as interferon production is crucial. Our work provides new insight into the mechanisms that convey the observed difference in viral and macrophage kinetics between HP and LP infections and establishes an improved model fitting framework to enhance the analysis of new data on viral pathogenicity. Author SummaryInfections with highly pathogenic (HP) influenza virus (e.g., the 1918 pandemic virus) often lead to serious morbidity and mortality. HP influenza virus infection is characterised by rapid viral growth rate, high viral load and excessive infiltration of macrophages to the lungs. Despite extensive study, we do not yet fully understand what biological processes leading to the observed viral and macrophage dynamics and therefore viral pathogenicity. Experimental studies have previously suggested that bot viral factors (e.g., viral proteins) and host factors (e.g., the host immune response) play a role to enhance viral pathogenicity. Here, we utilise in vivo kinetic data of viral load and macrophages and fit a viral dynamic model the data. Our model allow us to explore the biological mechanisms that contribute to the difference viral and macrophage dynamics between HP and LP infections. This study improves our understanding of the role of interferon on distinguishing immunodynamics between HP and LP infections. Our findings may contribute to the development of next-generation treatment which rely upon an understanding of the host different immunological response to HP influenza viruses.

immunology↗

A non-lemniscal thalamic interface connecting alerting sensory cues to internal states in mice

Alterations in internal states, such as elevated arousal level and increased anxiety or fear, triggered by alerting environmental cues are required for behavioral state transitions promoting survival. However, the specific brain region that plays an interfacing role between alerting stimuli and internal states remains to be identified. Here, we report that the medial sector of the auditory thalamus (ATm), which consists of a group of non-lemniscal thalamic nuclei, can fulfill this function. VGluT2-expressing ATm (ATmVGluT2+) neurons receive direct and strong inputs from both visual and auditory midbrain regions, and project to multiple downstream structures critically involved in brain state regulation. Their activity was correlated with, and indispensable for, both blue light- and sound-induced NREM sleep-to-Wake transition, and their arousing effects were mainly mediated by, but not limited to, the temporal association cortices. ATmVGluT2+ neuron activation in awake behaving mice induced pupil dilation and behavioral responses suggestive of anxiety. Blocking the neurotransmitter release of ATmVGluT2+ neurons receiving auditory inputs selectively abolished loud noise-triggered escape behavior but not locomotion. Thus, the ATm is an interface in mouse brain that can transform alerting environmental cues into internal arousal and emotional state alterations that promote survival.

neuroscience↗

Prediction of brain functions from structural connectome using graph neural network

AO_SCPLOWBSTRACTC_SCPLOWThe relationship between brain structure and function remains elusive, amidst the tremendous advances in brain mapping techniques. In this work, we attempt to partially disentangle this relationship by connecting task-evoked functional MRI (fMRI) responses with the underlying structural connectome using graph neural network (GNN). MRI data (n = 1,063) were collected from the Human Connectome Project. We demonstrate that our GNN-based model predicts task-evoked fMRI responses with high fidelity. Using a graph attention mechanism, it is possible to infer the subsets of neighboring cortical regions whose structural connections are important for the prediction of the functional responses of individual cortical regions. Notably, for each cortical region, such subset of neighboring cortical regions is predominantly localized to the ipsilateral hemisphere and much smaller than that with direct structural connections. We found that the higher cognitive functions subserved by the cingulo-opercular, dorsal attention, frontoparietal and default mode clusters may depend on neighboring cortical regions across a wide range of functional brain clusters in the ipsilateral hemisphere, whilst the sensory functions subserved by the visual1 and auditory clusters on neighboring cortical regions across much fewer functional brain clusters.

bioengineering↗

Structural basis for the assembly and electron transport mechanisms of the dimeric photosynthetic RC-LH1 supercomplex

The reaction center (RC) and light-harvesting complex 1 (LH1) form a RC-LH1 core supercomplex that is vital for the primary reactions of photosynthesis in purple photosynthetic bacteria. Some species possess the dimeric RC-LH1 complex with an additional polypeptide PufX, representing the largest photosynthetic complex in anoxygenic phototrophs. However, the details of the architecture and assembly mechanism of the RC-LH1 dimer are unclear. Here we report seven cryo-electron microscopy (cryo-EM) structures of RC-LH1 supercomplexes from Rhodobacter sphaeroides. Our structures reveal that two PufX polypeptides are positioned in the center of the S-shaped RC-LH1 dimer, interlocking association between the components and mediating RC-LH1 dimerization. Moreover, we identify a new transmembrane peptide, designated PufY, which is located between the RC and LH1 subunits near the LH1 opening. PufY binds a quinone molecule and prevents LH1 subunits from completely encircling the RC, creating a channel for quinone/quinol exchange. Genetic mutagenesis, cryo-EM structures, and computational simulations enable a mechanistic understanding of the assembly and electron transport pathways of the RC-LH1 dimer and elucidate the roles of individual components in ensuring the structural and functional integrity of the photosynthetic supercomplex.

biochemistry↗

Calcium-independent but voltage-dependent secretion (CiVDS) mediates synaptic transmission in a mammalian central synapse

A central principle of synaptic transmission is that action potential-induced presynaptic neurotransmitter release occurs exclusively via Ca2+-dependent secretion (CDS). The discovery and mechanistic investigations of Ca2+-independent but voltage-dependent secretion (CiVDS) have demonstrated that the action potential per se is sufficient to trigger neurotransmission in the somata of primary sensory and sympathetic neurons in mammals. One key question remains, however, whether CiVDS contributes to central synaptic transmission. Here we report, in the central transmission from presynaptic (dorsal root ganglion) to postsynaptic (spinal dorsal horn) neurons, (1) excitatory postsynaptic currents (EPSCs) are mediated by glutamate transmission through both CiVDS (up to 87%) and CDS; (2) CiVDS-EPSCs are independent of extracellular and intracellular Ca2+; (3) CiVDS is >100 times faster than CDS in vesicle recycling with much less short-term depression; (4) the fusion machinery of CiVDS includes Cav2.2 (voltage sensor) and SNARE (fusion pore). Together, an essential component of activity-induced EPSCs is mediated by CiVDS in a central synapse.

neuroscience↗

Structural basis for sterol sensing by Scap and Insig

The sterol regulatory element-binding protein (SREBP) pathway senses the cellular cholesterol level through sterol regulated association between Scap and Insig. Despite the recent structural determination of the transmembrane domains of human Scap and Insig-2 bound to 25-hydroxycholesterol (25HC), the structure and regulatory mechanism of the luminal domains of Scap by cholesterol remains elusive. Here, combining cryo-EM analysis and artificial intelligence-facilitated structural prediction, we report the structure of the human Scap/Insig-2 complex in the presence of digitonin instead of 25HC. Despite the lack of sequence similarity, the structure of the luminal domain Loop 1 and a co-folded segment in Loop 7 of Scap resembles that of the luminal/extracellular domain in NPC1 and related proteins. Comparison of the sterol-loaded structures of these proteins provides clues of the regulation of Loop 1/7 interaction by cholesterol. We also show that the structure of Scap(D428A), which suppresses SREBP activation under sterol depletion, is identical to WT when complexed with Insig-2, although the gain of function may also involve a later step in protein trafficking.

biochemistry↗

Transcriptomic encoding of sensorimotor transformation in the midbrain

Sensorimotor transformation, a process that converts sensory stimuli into motor actions, is critical for the brain to initiate behaviors. Although the circuitry involved in sensorimotor transformation has been well delineated, the molecular logic behind this process remains poorly understood. Here, we performed high-throughput and circuit-specific single-cell transcriptomic analyses of neurons in the superior colliculus (SC), a midbrain structure implicated in early sensorimotor transformation. We found that SC neurons in distinct laminae express discrete marker genes. Of particular interest, Cbln2 and Pitx2 are key markers that define glutamatergic projection neurons in the optic nerve (Op) and intermediate gray (InG) layers, respectively. The Cbln2+ neurons responded to visual stimuli mimicking cruising predators, while the Pitx2+ neurons encoded prey-derived vibrissal tactile cues. By forming distinct input and output connections with other brain areas, these neuronal subtypes independently mediate behaviors of predator avoidance and prey capture. Our results reveal that, in the midbrain, sensorimotor transformation for different behaviors may be performed by separate circuit modules that are molecularly defined by distinct transcriptomic codes.

neuroscience↗

Emergent myxobacterial behaviors arise from reversal suppression induced by kin contacts

A wide range of biological systems - from microbial swarms to bird flocks, display emergent behaviors driven by coordinated movement of individuals. To this end, individual organisms interact by recognizing their kin and adjusting their motility based on others around them. However, even in the best-studied systems, the mechanistic basis of the interplay between kin recognition and motility coordination is not understood. Here, using a combination of experiments and mathematical modeling, we uncover the mechanism of an emergent social behavior in Myxococcus xanthus. By overexpressing cell surface adhesins, TraA and TraB, involved in kin recognition, large numbers of cells adhere to one another and form organized macroscopic circular aggregates that spin clockwise or counterclockwise. Mechanistically, TraAB adhesion results in sustained cell-cell contacts that trigger cells to suppress cell reversals, and circular aggregates form as the result of cells ability to follow their own cellular slime trails. Furthermore, our in-silico simulations demonstrate a remarkable ability to predict self-organization patterns when phenotypically distinct strains are mixed. For example, defying naive expectations, both models and experiments found that strains engineered to overexpress different and incompatible traAB allelles nevertheless form mixed circular aggregates. Therefore, this work provides key mechanistic insights into M. xanthus social interactions and demonstrates how local cell contacts induce emergent collective behaviors by millions of cells. ImportanceIn many species, large populations exhibit emergent behaviors whereby all related individuals move in unison. For example, fish in schools can all dart in one direction simultaneously to avoid a predator. Currently, it is impossible to explain how such animals recognize kin through brain cognition and elicit such behaviors at a molecular level. However, microbes also recognize kin and exhibit emergent collective behaviors that are experimentally tractable. Here, using a model social bacterium, we engineer dispersed individuals to organize into synchronized collectives that create emergent patterns. With experimental and mathematical approaches we explain how this occurs at both molecular and population levels. The results demonstrate how the combination of local physical interactions triggers intracellular signaling, which in turn leads to emergent behavior on a population scale.

biophysics↗